PITX2 deficiency leads to atrial mitochondrial dysfunction

Jasmeet Reyat; Laura Sommerfeld; Molly O'Reilly; Victor Roth Cardoso; Ellen Thiemann; Abdullah Khan; Christopher O'Shea; Sönke  Harder; Christian  Müller; Jonathan Barlow; Rachel Stapley; Winnie Wei Ling Chua; Nashitha Kabir; Olivia Grech; Oliver Hummel; Norbert Hübner; Stefan Kaab; Lluis Mont; Stephane N Hatem; Joris Winters; Stef Zeemering; Neil Morgan; Julie Rayes; Katja Gehmlich; Monika Stoll; Theresa Brand; Michaela  Schweizer; Angelika Piasecki; Ulrich Schotten; Georgios Gkoutos; Kristina Lorenz; Friederike Cuello; Paulus Kirchhof; Larissa Fabritz

doi:10.1093/cvr/cvae169

PITX2 deficiency leads to atrial mitochondrial dysfunction

Jasmeet Reyat^*, Laura Sommerfeld, Molly O'Reilly, Victor Roth Cardoso, Ellen Thiemann, Abdullah Khan, Christopher O'Shea, Sönke Harder, Christian Müller, Jonathan Barlow, Rachel Stapley, Winnie Wei Ling Chua, Nashitha Kabir, Olivia Grech, Oliver Hummel, Norbert Hübner, Stefan Kaab, Lluis Mont, Stephane N Hatem, Joris WintersStef Zeemering, Neil Morgan, Julie Rayes, Katja Gehmlich, Monika Stoll, Theresa Brand, Michaela Schweizer , Angelika Piasecki, Ulrich Schotten, Georgios Gkoutos, Kristina Lorenz, Friederike Cuello, Paulus Kirchhof^*, Larissa Fabritz

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Aim. Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood.
Methods. To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls.
Results. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria.
Conclusions. In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.

Original language	English
Article number	cvae169
Journal	Cardiovascular Research
Early online date	12 Aug 2024
DOIs	https://doi.org/10.1093/cvr/cvae169
Publication status	E-pub ahead of print - 12 Aug 2024

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Reyat, J., Sommerfeld, L., O'Reilly, M., Roth Cardoso, V., Thiemann, E., Khan, A., O'Shea, C., Harder, S., Müller, C., Barlow, J., Stapley, R., Chua, W. W. L., Kabir, N., Grech, O., Hummel, O., Hübner, N., Kaab, S., Mont, L., Hatem, S. N., ... Fabritz, L. (2024). PITX2 deficiency leads to atrial mitochondrial dysfunction. Cardiovascular Research, Article cvae169. Advance online publication. https://doi.org/10.1093/cvr/cvae169

@article{d1a91048587d4138a688f9307169b8e4,

title = "PITX2 deficiency leads to atrial mitochondrial dysfunction",

abstract = "Aim. Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood. Methods. To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls. Results. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. Conclusions. In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.",

author = "Jasmeet Reyat and Laura Sommerfeld and Molly O'Reilly and {Roth Cardoso}, Victor and Ellen Thiemann and Abdullah Khan and Christopher O'Shea and S{\"o}nke Harder and Christian M{\"u}ller and Jonathan Barlow and Rachel Stapley and Chua, {Winnie Wei Ling} and Nashitha Kabir and Olivia Grech and Oliver Hummel and Norbert H{\"u}bner and Stefan Kaab and Lluis Mont and Hatem, {Stephane N} and Joris Winters and Stef Zeemering and Neil Morgan and Julie Rayes and Katja Gehmlich and Monika Stoll and Theresa Brand and Michaela Schweizer and Angelika Piasecki and Ulrich Schotten and Georgios Gkoutos and Kristina Lorenz and Friederike Cuello and Paulus Kirchhof and Larissa Fabritz",

year = "2024",

month = aug,

day = "12",

doi = "10.1093/cvr/cvae169",

language = "English",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

}

Reyat, J, Sommerfeld, L, O'Reilly, M, Roth Cardoso, V, Thiemann, E, Khan, A, O'Shea, C, Harder, S, Müller, C, Barlow, J, Stapley, R, Chua, WWL, Kabir, N, Grech, O, Hummel, O, Hübner, N, Kaab, S, Mont, L, Hatem, SN, Winters, J, Zeemering, S, Morgan, N , Rayes, J , Gehmlich, K, Stoll, M, Brand, T, Schweizer , M, Piasecki, A, Schotten, U, Gkoutos, G, Lorenz, K, Cuello, F, Kirchhof, P & Fabritz, L 2024, 'PITX2 deficiency leads to atrial mitochondrial dysfunction', Cardiovascular Research. https://doi.org/10.1093/cvr/cvae169

TY - JOUR

T1 - PITX2 deficiency leads to atrial mitochondrial dysfunction

AU - Reyat, Jasmeet

AU - Sommerfeld, Laura

AU - O'Reilly, Molly

AU - Roth Cardoso, Victor

AU - Thiemann, Ellen

AU - Khan, Abdullah

AU - O'Shea, Christopher

AU - Harder, Sönke

AU - Müller, Christian

AU - Barlow, Jonathan

AU - Stapley, Rachel

AU - Chua, Winnie Wei Ling

AU - Kabir, Nashitha

AU - Grech, Olivia

AU - Hummel, Oliver

AU - Hübner, Norbert

AU - Kaab, Stefan

AU - Mont, Lluis

AU - Hatem, Stephane N

AU - Winters, Joris

AU - Zeemering, Stef

AU - Morgan, Neil

AU - Rayes, Julie

AU - Gehmlich, Katja

AU - Stoll, Monika

AU - Brand, Theresa

AU - Schweizer , Michaela

AU - Piasecki, Angelika

AU - Schotten, Ulrich

AU - Gkoutos, Georgios

AU - Lorenz, Kristina

AU - Cuello, Friederike

AU - Kirchhof, Paulus

AU - Fabritz, Larissa

PY - 2024/8/12

Y1 - 2024/8/12

N2 - Aim. Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood. Methods. To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls. Results. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. Conclusions. In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.

AB - Aim. Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood. Methods. To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls. Results. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. Conclusions. In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.

UR - https://academic.oup.com/cardiovascres

U2 - 10.1093/cvr/cvae169

DO - 10.1093/cvr/cvae169

M3 - Article

SN - 0008-6363

JO - Cardiovascular Research

JF - Cardiovascular Research

M1 - cvae169

ER -

PITX2 deficiency leads to atrial mitochondrial dysfunction

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